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  • Publication
    Synergistic Effect of an Antisense Oligonucleotide and Small Molecule on Splicing Correction of the Spinal Muscular Atrophy Gene
    (Sage Journals, 2024-02-19) Ottesen, Eric ; Singh, Ravindra ; Biomedical Sciences ; College of Veterinary Medicine
    Spinal muscular atrophy (SMA) is treated by increasing the level of Survival Motor Neuron (SMN) protein through correction of SMN2 exon 7 skipping or exogenous expression of SMN through gene therapy. Currently available therapies have multiple shortcomings, including poor body-wide distribution, invasive delivery, and potential negative consequences due to high doses needed for clinical efficacy. Here we test the effects of a combination treatment of a splice-correcting antisense oligonucleotide (ASO) Anti-N1 with the small compounds risdiplam and branaplam. We show that a low-dose treatment of Anti-N1 with either compound produces a synergistic effect on the inclusion of SMN2 exon 7 in SMA patient fibroblasts. Using RNA-Seq, we characterize the transcriptomes of cells treated with each compound as well as in combination. Although high doses of each individual treatment trigger widespread perturbations of the transcriptome, combination treatment of Anti-N1 with risdiplam and branaplam results in minimal disruption of gene expression. For individual genes targeted by the 3 compounds, we observe little to no additive effects of combination treatment. Overall, we conclude that the combination treatment of a splice-correcting ASO with small compounds represents a promising strategy for achieving a high level of SMN expression while minimizing the risk of off-target effects.
  • Publication
    Seroprevalence of Senecavirus A in sows and grower-finisher pigs in major swine producing-states in the United States
    (Elsevier B.V., 2019-02-11) Houston, Elizabeth ; Giménez-Lirola, Luis ; Magtoto, Ronaldo ; Mora-Díaz, Juan Carlos ; Baum, David ; Piñeyro, Pablo Enrique ; Veterinary Diagnostic and Production Animal Medicine
    Senecavirus A (SVA) is a single-stranded RNA virus in the family Picornaviridae. Recently, SVA has been associated with idiopathic vesicular disease and increased neonate mortality outbreaks in the United States, Brazil, China, Colombia, and Thailand, with increasing incidence since 2014. Indirect detection by antibody detection methods, including indirect immunofluorescence assay (IFA), virus neutralization assay, and competitive or indirect enzyme-linked immunosorbent assays (ELISAs), have been reported in clinical and experimental trials. The objective of this study was to determine the seroprevalence of SVA in nonclinical affected herds in the United States. Individual samples were collected from 3654 and 2433 clinically healthy grower-finisher pigs and sows, respectively, from 219 unique commercial swine production sites. SVA seroprevalence was evaluated by SVA rVP1 ELISA and SVA IFA. The estimated seroprevalence for grower-finisher pigs and sows was 12.2% and 34.0%, respectively. The herd prevalence was 42.7% for grower-finisher farms and 75.8% for sow farms. The SVA rVP1 ELISA and SVA IFA exhibited a fair (sows) and moderate (grower-finisher) agreement at the herd level, while a fair agreement was observed at the individual level for both pig categories evaluated. The McNemar’s test was significant at the individual and herd level (p <  0.05). In this study, we demonstrated the presence of SVA IgG antibodies in pigs from clinically healthy grower-finisher and sow herds. These results suggest that SVA is circulating subclinically in sow farms and grower-finisher pig farms in major swine producing-states in the United States.
  • Publication
    Effects of calcined phosphogypsum replacement on hydration and properties of calcium sulfoaluminate cement at different curing temperatures
    (Taylor and Francis, 2024-02-13) Liao, Yishun ; Chen, Jiawen ; Yao, Jinxin ; Wang, Kejin ; Huang, Haoran ; Jiang, Guoxi ; Tang, Shengwen ; Zuo, Yibing ; Civil, Construction and Environmental Engineering
    The present research aims to understand the cement hydration and microstructure formation mechanism of calcined phosphogypsum (CPG) supplemented calcium sulfoaluminate (CSA) pastes cured under hot-weather temperatures and to ensure the appropriate application and effective service of CSA cement-based materials, as well as to address the problem of overstocking of CPG. The effects of CPG dosage on the heat of hydration, electrical resistivity, hydration products, and bound water content of CSA cement pastes were investigated at curing temperatures of 20 °C, 35 °C, and 50 °C. Hydration kinetics was studied to elucidate the hydration mechanism, and thermodynamic modelling was performed to predict the phase assemblages. The results show that the incorporation of CPG facilitated the formation of ettringite and significantly reduced the transformation of ettringite to monosulfate, and these phenomena were enhanced with an increase in the CPG. The addition of CPG at elevated curing temperature (35 °C and 50 °C) significantly improved the compressive strength of CSA cement pastes. The growth rate and nucleation rate predicted by the BNG model for the CSA cement pastes cured at 50 °C were substantially higher compared to those at 20 °C.
  • Publication
    Critical Responses of Flexible Pavements Under Superheavy Loads and Data-Driven Surrogate Model
    (Springer, 2022-01-18) Koh, Yongsung ; Ceylan, Halil ; Kim, Sunghwan ; Cho, In-Ho ; Civil, Construction and Environmental Engineering ; Institute for Transportation
    Superheavy Load (SHL), a specially-manufactured vehicle for transporting superheavy cargo such as wind turbines, has weight, size, and loading configurations that differ from general truck traffic, e.g., the 13 vehicle classes defined by Federal Highway Administration (FHWA). To characterize non-generic configurations of SHLs, an innovative analysis method is needed to predict unexpected damages that can be occurred in flexible pavement subjected to SHL loading. In this paper, existing methodologies including the superposition method and the nucleus segment approach are introduced to characterize the loading range and magnitude of each SHL. To identify potential damages by SHLs on flexible pavement, a set of experimental matrices considering pavement properties and loadings from the nucleus segment of each SHL is established - i.e., a total of 3,456 cases of flexible pavement analysis, varying in thickness and modulus of elasticity of each layer, and in types of loading, are performed using a Layered Elastic Theory (LET)-based analysis program, MnLayer. As a result of the mechanistic investigation, critical pavement responses under SHLs and FHWA class 9 truck (reference vehicle) are determined. Furthermore, damage ratios using transfer functions available in Mechanistic- Empirical Pavement Design Guide (MEPDG): A Manual of Practice are calculated for each SHL compared to the reference vehicle, FHWA class 9 truck. Finally, an advanced statistical prediction model, Generalized Additive Model (GAM), is constructed as a data-driven surrogate model to provide relatively high performance in predicting target responses of flexible pavements from varying explanatory variables (e.g., flexible pavement properties and loading conditions of SHLs).
  • Publication
    In Vitro Evaluation of Essential Oils and Saturated Fatty Acids for Repellency against the Old-World Sand Fly, Phlebotomus papatasi (Scopoli) (Diptera: Psychodidae)
    (Multidisciplinary Digital Publishing Institute, 2024-02-24) Temeyer, Kevin B. ; Schlechte, Kristie G. ; Coats, Joel ; Cantrell, Charles L. ; Rosario-Cruz, Rodrigo ; Lohmeyer, Kimberly H. ; Pérez de León, Adalberto A. ; Li, Andrew Y. ; Plant Pathology, Entomology and Microbiology
    The sand fly, Phlebotomus papatasi (Scopoli, 1786), is a major vector for Leishmania major in the Middle East, which has impacted human health and US military operations in the area, demonstrating the need to develop effective sand fly control and repellent options. Here, we report the results of spatial repellency and avoidance experiments in a static air olfactometer using the female P. papatasi testing essential oils of Lippia graveolens (Mexican oregano), Pimenta dioica (allspice), Amyris balsamifera (amyris), Nepeta cataria (catnip), Mentha piperita (peppermint), and Melaleuca alternifolia (tea tree); the 9–12 carbon saturated fatty acids (nonanoic acid, decanoic acid, undecanoic acid, and dodecanoic acid); and the synthetic repellents DEET and IR3535. The materials applied at 1% exhibited varying activity levels but were not significantly different in mean repellency and avoidance from DEET and IR3535, except in regards to nonanoic acid. Some materials, particularly nonanoic and undecanoic acids, produced sand fly mortality. The observed trends in mean repellency over exposure time included the following: (1) P. dioica oil, M. alternifolia oil, decanoic acid, undecanoic acid, DEET, and IR3535 exhibited increasing mean repellency over time; (2) oils of N. cataria, A. balsamifera, M. piperita, and dodecanoic acid exhibited relatively constant mean repellency over time; and (3) L. graveolens oil and nonanoic acid exhibited a general decrease in mean repellent activity over time. These studies identified the essential oils of N. cataria and A. balsamifera as effective spatial repellents at reduced concentrations compared to those of DEET. Additional research is required to elucidate the modes of action and potential synergism of repellents and essential oil components for enhanced repellency activity.